The objective of this project is to establish a small animal model of leukoencephalopathy (white matter necrosis) caused by methotrexate (MTX) and ionizing radiation. The specific aims are to identify and characterize the interactions between MTX and ionizing radiation which produce white matter necrosis, and to test hypotheses which suggest methods to prevent leukoencephalopathy in man. The target tissue will be the cervical white matter in rats and the clinical end-point will be foreleg paresis. MTX will be infused into the cerebral ventricles via indwelling subcutaneous osmotic minipumps and the cervical spinal cord will be irradiated with cesium-137 at a dose rate of 100 rad/min. The dose effect factor (DEF) of intraventricular MTX will be assessed by shifts in the dose-effect curves generated by single radiation doses in the 1800-3000 rad range. The DEF will be determined for MTX administered before, during and after radiation, and all overt neurotoxicity will be confirmed by histopathological examination. MTX concentrations in the spinal cord, brain, ventricular and spinal fluids and serum will be measured with the dihydrofolate reductase inhibition assay. The experiments will be repeated with fractionated radiation, in the 180-300 rad/day range. A reduction in the DEF will be attempted with pretreatment and concurrent administration of 5-methyltetrahydrofolate, choline, or L-DOPA. The ultimate goal is to determine methods which can prevent leukoencephalopathy without compromising the therapeutic effect of MTX and radiation. MTX administered intrathecally or in high doses intravenously is an effective therapy in the treatment of CNS leukemia, lymphoma and brain tumors; yet medical and radiation oncologists have come to avoid it because of the fear of leukoencephalopathy. Approximately half of all childhood malignancies and 10% of adult cancers are at stake, and any significant improvement in the therapeutic index of MTX and ionizing radiation would result in a substantial advance in cancer clinical treatment.